Cdk5/p25 specific inhibitory peptide TFP5 rescues the loss of dopaminergic neurons in a sub-acute MPTP induced PD mouse model

Neurosci Lett. 2016 Oct 6;632:1-7. doi: 10.1016/j.neulet.2016.08.023. Epub 2016 Aug 16.

Abstract

Parkinson's disease (PD) is pathologically characterized by progressively loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the formation of Lewy bodies. In 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) induced PD mice models, the calpain- cyclin-dependent kinase 5 (Cdk5)-myocyte enhancer factor 2 (MEF2) signaling has been proven in governing dopaminergic neuronal death. Under MPTP insult, p35 is cleaved by calpain into p25, which binds to Cdk5 and exhibits hyperactivity of Cdk5/p25. Cdk5/p25 inactivates MEF2, a survivor factor, which is critical for DA neuronal death. In this study, neuroprotective effect of the Cdk5/p25 specific peptide, TFP5, was evaluated in sub-acute MPTP induced PD mouse model by intraperitoneal (i.p.) injection of MPTP for five consecutive days. The results indicated that the levels of p35 and p25, and p25/p35 ratio increased in the sub-acute MPTP mice. TFP5 broadly reached cortex neuron, hippocampus and SNpc areas after i.p. injections. Pretreatment with 45mg/kg/day TFP5, as well as 10mgkg/day Cdk5 inhibitor roscovitine, for three days significantly rescued DA neuronal loss up to 9.8% or 9.7% respectively compared to the saline treated group. Treatment of TFP5 and roscovitine reduced the levels of inactive form of MEF2 and cleaved caspase 3, thus protected apoptosis of DA neurons against MPTP insult. Our results propose that TFP5 might be a potential therapeutic candidate for PD.

Keywords: Cyclin-dependent kinase 5; Dopaminergic neurons; MEF2; MPTP; Parkinson’s disease; TFP5.

MeSH terms

  • Animals
  • Cell Death / drug effects*
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Cyclin-Dependent Kinase 5 / metabolism*
  • Dopaminergic Neurons / drug effects*
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Mice
  • Neuroprotective Agents / pharmacology
  • Parkinsonian Disorders / metabolism
  • Parkinsonian Disorders / pathology*

Substances

  • Neuroprotective Agents
  • Cyclin-Dependent Kinase 5